Compounds and compositions as itpkb inhibitors

Abstract

The invention provides a novel class of compounds, pharmaceutical compositions comprising such compounds and methods of using such compounds to treat or prevent diseases or disorders associated with abnormal or deregulated B cell activities, particularly diseases or disorders that involve aberrant activation of inositol 1,4,5-trisphosphate 3-kinase B (ITPKb).

1 - 57 . (canceled) 
     
     
         58 . A compound of Formula (I), or pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof: 
       
         
           
           
               
               
           
         
         wherein:
 L 1  is —(CR 11 R 12 ) p —, —C(O)—, or —S(O) 2 —; 
 L 2  is —C(O)—, —C(O)NR 5 — or —NR 5 C(O; 
 Y is N or CR 4 ; 
 each R 1  is independently selected from —C(O)R 9 , C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, aryl, heteroaryl, C 3 -C 8 cycloalkyl, and C 3 -C 10 heterocycloalkyl, wherein the C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, aryl, heteroaryl, C 3 -C 8 cycloalkyl, and C 3 -C 10 heterocycloalkyl groups of R 1  are each optionally substituted with 1 to 3 substituents independently selected from halogen, —CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxyl, C 3 -C 8 cycloalkyl, C 3 -C 10 heterocycloalkyl, —OR 9 , —C(O)R 9 , —OC(O)R 9 , —C(O)OR 9 , —N(R 6 R 7) , —C(O)N(R 6 R 7 ), —S(O) 2 R 9 , —S(O) 2 N(R 6 R 7 ), and —NR 7 S(O) 2 R 9 ; 
 or two R 1  groups are each independently C 1 -C 4 alkyl and form a C 1 -C 4 alkyl bridge, or two R 1  groups are each independently C 1 -C 4 alkyl and taken together with the C atom to which they are attached form an optionally substituted C 3 -C 8 cycloalkyl; 
 each R 2  is independently selected from halogen, —CN, —OR 9 , —C(O)R 9 , —C(O)N(R 6 R 7 ), C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, aryl, heteroaryl, C 3 -C 8 cycloalkyl, and C 3 -C 10 heterocycloalkyl, wherein the C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, aryl, heteroaryl, C 3 -C 8 cycloalkyl, and C 3 -C 10 heterocycloalkyl groups of R 2  are each optionally substituted with 1 to 3 substituents independently selected from halogen, —CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6  alkoxy, C 1 -C 6 haloalkoxyl, C 3 -C 8 cycloalkyl, C 3 -C 10 heterocycloalkyl, —OR 9 , —C(O)R 9 , —OC(O)9-C(O)OR 9 , —N(R 6 R 7 ), —C(O)N(R 6 R 7 ), —S(O) 2 R 9 , —S(O) 2 N(R 6 R 7 ), and —NR 7 S(O) 2 R 9 ; 
 when Y is N then R 3  is selected from L 2 -R 10 , C 1 -C 6 alkyl, C 2 -C 8 alkene, C 2 -C 8 alkyne, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 3 -C 8 cycloalkyl, C 3 -C 10 heterocycloalkyl, C 6-10 aryl and C 2 -C 9 heteroaryl, wherein the C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 2 -C 9 heteroaryl, C 3 -C 8 cycloalkyl, aryl and C 3 -C 10 heterocycloalkyl groups of R 3  are each optionally substituted with 1 to 3 substituents independently selected from halogen, —CN, R 8 , —OR 9 , —C(O)R 9 , —OC(O)R 9 , —C(O)OR 9 , —N(R 6 R 7 ), —NR 6 C(O)R 7 , —C(O)N(R 6 R 7 ), —S(O) 2 R 9 , —S(O) 2 N(R 6 R 7 ) and —NR 7 S(O) 2 R 9 ; 
 when Y is CR 4  then R 3  is selected from L 2 -R 10 , C 1 -C 6 alkyl, C 2 -C 8 alkene, C 2 -C 8 alkyne, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 3 -C 8 cycloalkyl, C 3 -C 10 heterocycloalkyl and C 2 -C 9 heteroaryl, provided that R 3  is not a six-membered heteroaryl containing 1 to 3 N atoms, and wherein the C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 2 -C 9 heteroaryl, C 3 -C 8 cycloalkyl and C 3 -C 10 heterocycloalkyl groups of R 3  are each optionally substituted with 1 to 3 substituents independently selected from halogen, —CN, R 8 , —OR 9 , —C(O)R 9 , —OC(O)R 9 , —C(O)OR 9 , —N(R 6 R 7 ), —NR 6 C(O)R 7 , —C(O)N(R 6 R 7 ), —S(O) 2 R 9 , —S(O) 2 N(R 6 R 7 ) and —NR 7 S(O) 2 R 9 ; 
 R 4  is selected from H, —C(O)OR 9 , —C(O)R 9 , —C(O)N(R 6 R 7 ), —N(R 6 R 7 ), —NR 6 C(O)R 7 , —(CH 2 ) n OR 7 , C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, C 2 -C 8 alkene, C 2 -C 8 alkyne, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, aryl, heteroaryl, C 3 -C 8 cycloalkyl, and C 3 -C 10 heterocycloalkyl, wherein the C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, C 2 -C 8 alkene, C 2 -C 8 alkyne, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, aryl, heteroaryl, C 3 -C 8 cycloalkyl, and C 3 -C 10 heterocycloalkyl groups of R 5  are each optionally substituted with 1 to 3 substituents independently selected from halogen, —CN, —R 8 , —OR 9 , —C(O)R 9 , —OC(O)R 9 , —C(O)OR 9 , —N(R 6 R 7 ), —C(O)N(R 6 R 7 ), —S(O) 2 R 9 , —S(O) 2 N(R 6 R 7 ), and —NR 7 S(O) 2 R 9 ; 
 R 5 , R 6  and R 7  are each independently selected from H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl, C 3 -C 10 heterocycloalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, aryl and heteroaryl, wherein the C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl, C 3 -C 10 heterocycloalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, aryl and heteroaryl of R 5 , R 6  and R 7  are each optionally substituted with 1 to 3 substituents independently selected from halogen, —CN, —R 8 , —OR 9 , —C(O)R 9 , —OC(O)R 9 , —C(O)OR 9 , —N(R 6 R 7 ), —C(O)N(R 6 R 7 ), —S(O) 2 R 9 , —S(O) 2 N(R 6 R 7 ), and —NR 7 S(O) 2 R 9 , 
 or R 6  and R 7  are each independently C 1 -C 4 alkyl and taken together with the C atom to which they are attached form a C 3 -C 8 cycloalkyl; 
 R 8  is selected from H, CN, —OR 9 , —C(O)R 9 , —C(O)OR 9 , —C(O)N(R 6 R 7 ), —C(═NH)N(R 6 R 7 ), C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 3 -C 8 cycloalkyl, and C 3 -C 10 heterocycloalkyl; 
 R 9  is selected from H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl, C 3 -C 10 heterocycloalkyl, C 1 -C 6 haloalkyl and C 1 -C 6 haloalkoxy; 
 R 10  is selected from C 1 -C 6 alkyl, C 2 -C 8 alkene, C 2 -C 8 alkyne, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, aryl, heteroaryl, C 3 -C 8 cycloalkyl, and C 3 -C 10 heterocycloalkyl, wherein the C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, aryl, heteroaryl, C 3 -C 8 cycloalkyl, and C 3 -C 10 heterocycloalkyl groups of R 10  are each optionally substituted with 1 to 3 substituents independently selected from halogen, —CN, R 8 , —OR 9 , —C(O)R 9 , —OC(O)R 9 , —C(O)OR 9 , —N(R 6 R 7 ), —C(O)N(R 6 R 7 ), —S(O) 2 R 7 , —S(O) 2 N(R 6 R 7 ) and —NR 7 S(O) 2 R 9 ; 
 R 11  and R 12  are each independently selected from H, C 1 -C 4 alkyl, C 1 -C 4 heteroalkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy and C 1 -C 4 haloalkoxy; 
 or R 11  and R 12  are each independently C 1 -C 4 alkyl and taken together with the C atom to which they are attached form a C 3 -C 8 cycloalkyl; 
 m is, independently at each occurrence, 0, 1, 2, 3 or 4; 
 n is, independently at each occurrence, 0, 1, 2, 3 or 4, and 
 p is, independently at each occurrence, 1, 2, 3 or 4. 
 
       
     
     
         59 . The compound of  claim 58 , wherein the compound of Formula (I) has a structure of Formula (II): 
       
         
           
           
               
               
           
         
       
     
     
         60 . The compound of  claim 59 , wherein n is 0, 1 or 2 and m is 0, 1 or 2. 
     
     
         61 . The compound of  claim 60 , wherein the compound has a structure of Formula (III), Formula (IV) or Formula (V): 
       
         
           
           
               
               
           
         
       
     
     
         62 . The compound of  claim 61 , wherein L 1  is —(CR 11 R 12 ) p —, p is 1 or 2, and R 11  and R 12  are each independently selected from H and C 1 -C 4 alkyl. 
     
     
         63 . The compound of  claim 62 , wherein L 1  is —(CH 2 )—. 
     
     
         64 . The compound of  claim 63 , wherein the compound has a structure of Formula (VI), Formula (VII), Formula (VIII), Formula (IX), Formula (X) or Formula (XI): 
       
         
           
           
               
               
           
         
       
     
     
         65 . The compound of  claim 64 , wherein R 1  is C 1 -C 6 alkyl or C 1 -C 6 haloalkyl. 
     
     
         66 . The compound of  claim 65 , wherein R 2  is C 1 -C 6 alkyl or C 1 -C 6 haloalkyl. 
     
     
         67 . The compound of  claim 66 , wherein R 1  is methyl, ethyl, trifluoromethyl, difluoromethyl or fluoromethyl. 
     
     
         68 . The compound of  claim 67 , wherein R 2  is methyl, ethyl, trifluoromethyl, difluoromethyl or fluoromethyl. 
     
     
         69 . The compound of  claim 68 , wherein the compound has a structure of Formula (XII), Formula (XIII), Formula (XIV), Formula (XV), Formula (XVI), Formula (XVII), Formula (XVIII) or Formula (XIX): 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         70 . The compound of  claim 69 , wherein R 3  is C 3 -C 10 heterocycloalkyl or C 2 -C 9 heteroaryl, wherein the C 3 -C 10 heterocycloalkyl and C 2 -C 9 heteroaryl groups of R 3  are each optionally substituted with 1 to 3 substituents independently selected from halogen, —CN, R 8 , —OR 9 , —C(O)R 9 , —OC(O)R 9 , —C(O)OR 9 , —N(R 6 R 7 ), —C(O)N(R 6 R 7 ), —S(O) 2 R 9 , —S(O) 2 N(R 6 R 7 ) and —NR 7 S(O) 2 R 9  and provided that R 3  is not a six-membered heteroaryl containing 1 to 3 N atoms. 
     
     
         71 . The compound of  claim 70 , wherein R 3  is selected from oxo-1,2-dihydropyridine, 4,5,6,7-tetrahydro-1H-benzo[d]imidazolyl, 5,6-dihydropyridin-1(2H)-yl, 1,2,3,6-tetrahydropyridin-4-yl, piperidinyl, benzimidazolyl, furyl, imidazolyl, imidazo[4,5-c]pyridinyl, indolyl, isoquinolinyl, pyrazolyl, pyrrolyl, pyrrolo[2,3-b]pyridinyl and thienyl. 
     
     
         72 . The compound of  claim 71 , wherein R 3  is substituted with 1 to 3 substituents independently selected from halogen and R 8  , wherein R 8  is selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, H, —CN, —OR 9 , —C(O)R 9 , —C(O)OR 9 , —C(O)N(R 6 R 7 ), and —C(═NH)N(R 6 R 7 ). 
     
     
         73 . The compound of  claim 72 , wherein R 3  is selected from isoquinoline, 2-oxo-1,2-dihydropyridine-4-carbonitrile, thiophene, pyrrole, 1H-pyrrole-3-carbonitrile, benzimidazole, 5-fluoro-1H-benzo[d]imidazole, 4,5,6,7-tetrahydro-1H-benzo[d]imidazole, imidazole, 5-methyl-1H-imidazole, 4,5-dimethyl-1H-imidazole, 4-cyano-1H-pyrazole, 1H-imidazo[4,5-c]pyridine, 4-(trifluoromethyl)-1H-imidazole, 1H-benzo[d]imidazole-5-carbonitrile, 1H-imidazole-4-carbonitrile, 1H-pyrrole-3-carboxamide, 1H-pyrrole-2-carboxamide, 1H-pyrrole-2-carbonitrile, furan-2-carboxylic acid, furan-2-carboxamide, furan-3-carboxylic acid, furan-3-carboxamide, furan-2-carboxylate, methyl furan-2-carboxylate, N-methyl-1H-pyrrole-3-carboxamide, 1H-pyrrolo[2,3-b]pyridine, N,N-dimethyl-1H-pyrrole-3-carboxamide, N-(2-hydroxypropyl)-1H-pyrrole-3-carboxamide, (S)—N-(1-hydroxypropan-2-yl)-1H-pyrrole-3-carboxamide, 1H-indole, N-(2-hydroxyethyl)-1H-pyrrole-3-carboxamide, 1,2,3,6-tetrahydropyridine, 5,6-dihydropyridine-1(2H)-carbaldehyde, 1-(5,6-dihydropyridin-1(2H)-yl)ethanone, piperidine, 1-(piperidin-1-yl)ethanone, piperidine-1-carbaldehyde, 1H-imidazole-4-carboximidamide and 1H-imidazole-4-carboxamide. 
     
     
         74 . The compound of  claim 73 , wherein R 3  is L 2 -R 10 . 
     
     
         75 . The compound of  claim 74 , wherein L 2  is selected from C 1 -C 6 alkenylene, —C(O)— and —C(O)NR 5 —. 
     
     
         76 . The compound of  claim 75 , wherein R 10  is selected from aryl, heteroaryl and C 3 -C 10 heterocycloalkyl, wherein the aryl, heteroaryl and C 3 -C 10 heterocycloalkyl groups of R 10  are each optionally substituted with 1 to 3 substituents independently selected from halogen, —CN, R 8 , —OR 9 , —C(O)R 9 , —OC(O)R 9 , —C(O)OR 9 , —N(R 6 R 7 ), —C(O)N(R 6 R 7 ), —S(O) 2 R 7 , —S(O) 2 N(R 6 R 7 ) and —NR 7 S(O) 2 R 9 . 
     
     
         77 . The compound of  claim 76 , wherein L 2  is —C(O)NR 5 — and R 10  is selected from 1H-indole, pyridine, 1H-imidazole-5-carbonitrile and 1H-pyrazole-4-carbonitrile. 
     
     
         78 . The compound of  claim 77 , wherein L 2  is —C(O)— and R 10  is selected from azetidin-3-ol, pyrrolidin-3-ol and piperidin-4-ol. 
     
     
         79 . The compound of  claim 58  selected from:
 (R)-4-((3-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methyl)-N-(pyridin-4-yl)-1H-pyrazole-3-carboxamide; (R)-5-(4-((3-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methyl)-1H-pyrazol-3-yl)-1H-pyrrole-3-carbonitrile; (R)-5-(4-((3-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methyl)-1H-pyrazol-3-yl)-1H-pyrrole-3-carboxamide; (R)—N-methyl-5-(4-((3-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methyl)-1H-pyrazol-3-yl)-1H-pyrrole-3-carboxamide; (R)-5-(4-((3-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methyl)-1H-pyrazol-3-yl)-1H-pyrrole-2-carbonitrile; (R)-5-(4-((3-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methyl)-1H-pyrazol-3-yl)-1H-pyrrole-2-carboxamide; (R)-4-(4-((3-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methyl)-1H-pyrazol-3-yl)-1H-pyrrole-2-carbonitrile; (R)-4-(4-((3-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methyl)-1H-pyrazol-3-yl)-1H-pyrrole-2-carboxamide; (R)-2-(4-((3-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methyl)-1H-pyrazol-3-yl)-1H-indole; (R)-2-methyl-4-((3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazol-4-yl)methyl)-1-(5-(trifluoromethyl)pyridin-2-yl)piperazine; (R)-4-(4-((3-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methyl)-1H-pyrazol-3-yl)-5,6-dihydropyridine-1(2H)-carbaldehyde; (R)-2-methyl-4-((3-(4-(trifluoromethyl)-1H-imidazol-2-yl)-1H-pyrazol-4-yl)methyl)-1-(5-(trifluoromethyl)pyridin-2-yl)piperazine; (R)-2-(4-((3-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methyl)-1H-pyrazol-3-yl)-1H-imidazole-4-carboximidamide; (R)-2-(4-((3-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methyl)-1H-pyrazol-3-yl)-1H-imidazo[4,5-c]pyridine; (R,Z)-5-((4-((3-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methyl)-1H-pyrazol-3-yl)methylene)imidazolidine-2,4-dione; (R)-6-(4-((3-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methyl)-1H-pyrazol-3-yl)isoquinoline; (R)-6-(4-((3-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methyl)-1H-pyrazol-3-yl)-2-oxo-1,2-dihydropyridine-3-carbonitrile; 1-((3-(thiophen-2-yl)-1H-pyrazol-4-yl)methyl)-4-(5-(trifluoromethyl)pyridin-2-yl)piperazine; (R)-2-(4-((3-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methyl)-1H-pyrazol-3-yl)-1H-benzo[d]imidazole; (R)-2-methyl-4-((3-(5-methyl-1H-imidazol-2-yl)-1H-pyrazol-4-yl)methyl)-1-(5-(trifluoromethyl)pyridin-2-yl)piperazine; (R)-4-((3-(4,5-dimethyl-1H-imidazol-2-yl)-1H-pyrazol-4-yl)methyl)-2-methyl-1-(5-(trifluoromethyl)pyridin-2-yl)piperazine; (R)-2-(4-((3-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methyl)-1H-pyrazol-3-yl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazole; (R)-5-fluoro-2-(4-((3-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methyl)-1H-pyrazol-3-yl)-1H-benzo[d]imidazole; (R)-2-(4-((3-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methyl)-1H-pyrazol-3-yl)-1H-benzo[d]imidazole-5-carbonitrile; (S)-5-(4-((3-(trifluoromethyl)-4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methyl)-1H-pyrazol-3-yl)-1H-pyrrole-3-carbonitrile; (R)—N-(5-cyano-1H-imidazol-4-yl)-4-((3-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methyl)-1H-pyrazole-3-carboxamide; (R)—N-(4-cyano-1H-pyrazol-3-yl)-4-((3-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methyl)-1H-pyrazole-3-carboxamide; (R)-(3-hydroxyazetidin-1-yl)(4-((3-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methyl)-1H-pyrazol-3-yl)methanone; (3-hydroxypyrrolidin-1-yl)(4-(((R)-3-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methyl)-1H-pyrazol-3-yl)methanone; (R)-(4-hydroxypiperidin-1-yl)(4-((3-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methyl)-1H-pyrazol-3-yl)methanone; (R)-methyl 5-(4-((3-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methyl)-1H-pyrazol-3-yl)furan-2-carboxylate; (R)-5-(4-((3-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methyl)-1H-pyrazol-3-yl)furan-2-carboxylic acid; (R)-5-(4-((3-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methyl)-1H-pyrazol-3-yl)furan-2-carboxamide; (R)-4-(4-((3-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methyl)-1H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridine; (R)—N,N-dimethyl-5-(4-((3-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methyl)-1H-pyrazol-3-yl)-1H-pyrrole-3-carboxamide; (R)—N-(2-hydroxyethyl)-5-(4-((3-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methyl)-1H-pyrazol-3-yl)-1H-pyrrole-3-carboxamide; N-(2-hydroxypropyl)-5-(4-(((R)-3-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methyl)-1H-pyrazol-3-yl)-1H-pyrrole-3-carboxamide; (R)-3-(4-((3-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methyl)-1H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridine; N—((S)-1-hydroxypropan-2-yl)-5-(4-(((R)-3-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methyl)-1H-pyrazol-3-yl)-1H-pyrrole-3-carboxamide; (R,Z)-5-((4-((3-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methyl)-1H-pyrazol-3-yl)methylene)-2-thioxoimidazolidin-4-one; (R)-1-(4-(4-((3-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methyl)-1H-pyrazol-3-yl)-5,6-dihydropyridin-1(2H)-yl)ethanone; (R)-2-methyl-4-((3-(piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-1-(5-(trifluoromethyl)pyridin-2-yl)piperazine; (R)-4-(4-((3-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methyl)-1H-pyrazol-3-yl)piperidine-1-carbaldehyde; (R,Z)-2-imino-5-((4-((3-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methyl)-1H-pyrazol-3-yl)methylene)imidazolidin-4-one; (S)-5-(4-((3-(trifluoromethyl)-4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methyl)-1H-pyrazol-3-yl)-1H-pyrrole-3-carboxamide; (R)-5-(4-((3-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methyl)-1H-pyrazol-3-yl)furan-3-carboxylic acid; (R)-5-(4-((3-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methyl)-1H-pyrazol-3-yl)furan-3-carboxamide; (R)-2-(4-((3-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methyl)-1H-pyrazol-3-yl)-1H-imidazole-4-carbonitrile; (R)-2-(4-((3-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methyl)-1H-pyrazol-3-yl)-1H-imidazole-4-carboxamide; (R)-4-(5-((3-methyl-4-(4-(trifluoromethyl)phenyl)piperazin-1-yl)methyl)-2H-1,2,3-triazol-4-yl)benzonitrile. (R)-6-(4-((3-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methyl)-1H-pyrazol-3-yl)-2-oxo-1,2-dihydropyridine-4-carbonitrile; (R)-4-((3-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methyl)-N-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-1H-pyrazole-3-carboxamide; (R)-4-((3-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methyl)-N-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-1H-pyrazole-3-carboxamide; (R)-4-((3-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methyl)-N-(4-(N-(5-methylisoxazol-3-yl)sulfamoyl)phenyl)-1H-pyrazole-3-carboxamide; (R)-3-(4-((3-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methyl)-1H-pyrazol-3-yl)-1H-indole, and (R)-4-(5-((3-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methyl)-2H-1,2,3-triazol-4-yl)benzonitrile. 
 
     
     
         80 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I) of  claim 58  and a pharmaceutically acceptable carrier. 
     
     
         81 . A method for treating a disease or disorder where modulation of B lymphocyte development and function is implicated, comprising administering to a human in need of such treatment an effective amount of a compound of Formula (I) of  claim 58 , or pharmaceutically acceptable salts or pharmaceutical compositions thereof. 
     
     
         82 . The method of  claim 81 , wherein the disease or condition is an autoimmune disease. 
     
     
         83 . The method of  claim 82 , wherein the autoimmune disease is rheumatoid arthritis, systemic lupus erythematosus, idiopathic thrombocytopenic purpura, hemolytic anemia, or psoriasis. 
     
     
         84 . A method for treating a cell-proliferative condition, comprising administering to a human in need of such treatment an effective amount of a compound of Formula (I) of  claim 58 , or pharmaceutically acceptable salts or pharmaceutical compositions thereof; wherein the cell-proliferative condition is lymphoma. 
     
     
         85 . The method of  claim 84 , wherein the lymphoma is B cell lymphoma.